Niall Tubridy

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self‐antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4+ T cells that secrete interleukin (IL)‐17, termed Th17, but also IL‐17‐secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL‐17‐producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8+ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.

Despite the fact that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in maintaining self-tolerance and that IL-17-producing CD4+ T cells (Th17 cells) are pathogenic in many autoimmune diseases, evidence to date has indicated that Th17 cells are resistant to suppression by human Foxp3+ Treg cells. It was recently demonstrated that CD39, an ectonucleotidase which hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found that although both CD4+CD25highCD39+ and CD4+CD25highCD39− T cells suppressed proliferation and IFN-γ production by responder T cells, only the CD4+CD25highCD39+, which were predominantly FoxP3+, suppressed IL-17 production, whereas CD4+CD25highCD39− T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4+CD25+CD127lowFoxP3+, but interestingly a deficit in the relative frequency and the suppressive function of CD4+CD25+CD127lowFoxP3+CD39+ Treg cells. The mechanism of suppression by CD39+ Treg cells appears to require cell contact and can be duplicated by adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our findings suggest that CD4+CD25+Foxp3+CD39+ Treg cells play an important role in constraining pathogenic Th17 cells and their reduction in multiple sclerosis patients might lead to an inability to control IL-17 mediated autoimmune inflammation.

Gait and balance impairment in early multiple sclerosis in the absence of clinical disability

This study evaluated the gait and balance performance of two clinically distinct groups of recently diagnosed and minimally impaired multiple sclerosis (MS) patients (Expanded Disability Status Scale range 0- 2.5), compared to control subjects. Ten MS patients with mild pyramidal signs (Pyramidal Functional Systems 1.0), 10 MS patients with no pyramidal signs (Pyramidal Functional Systems 0) and 20 age- and gender-matched control subjects were assessed using laboratory-based gait analysis and clinical balance measures. Both MS groups demonstrated reduced speed and stride length (P < 0.001), and prolonged double limb support (P<0.02), compared to the control group, along with alterations in the timing of ankle muscle activity, and the pattern of ankle motion during walking, which occurred independent of gait speed. The pyramidal MS group walked with reduced speed (P=0.03) and stride length (P=0.04), and prolonged double limb support (P=0.01), compared to the non-pyramidal group. Both MS groups demonstrated concomitant balance impairment, performing poorly on the Functional Reach Test compared to the control group (P<0.05). The identification of incipient gait and balance impairment in MS patients with recent disease onset suggests that motor function may begin to deteriorate in the early stages of the disease, even in the absence of clinical signs of pyramidal dysfunction.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of ‘true’ association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 × 10−8) evidence of an association between KIAA0350 and risk of disease.

Improving interobserver variation in reporting gadolinium-enhanced MRI lesions in multiple sclerosis

Gadolinium-enhanced MRI is a sensitive and objective means to monitor disease activity in multiple sclerosis (MS). We evaluated the interobserver agreement and the value of observer training in reporting enhancing lesions from serial MRI. Scans of 16 MS patients were evaluated by five inexperienced and five experienced observers before and after consensus formation and training. The number of lesions at baseline, and the number of new and persistent lesions at follow-up were scored. For each condition, weighted kappa values (κ) and the mean average difference to the median (MADM) scores were calculated. Without training, the experienced readers showed good agreement on number of lesions at baseline and new lesions at follow-up, and moderate agreement for persistent lesions. The inexperienced readers showed poor agreement for baseline and persistent lesions, and moderate agreement for new lesions. After training, both groups reported lower absolute numbers of lesions, especially the inexperienced readers. The experienced readers showed good agreement for all lesion types, the inexperienced readers showed agreement for baseline and new lesions, and agreement was moderate for persistent lesions. In both groups MADM scores were <0.72 for baseline and new lesions, but >1.2 for persistent lesions. Interobserver agreement is improved by training, especially in inexperienced readers. Interobserver agreement in reporting gadolinium-enhanced lesions is high, which validates the use of serial, enhanced MRI as an outcome parameter in treatment trials in MS.

IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells

Interferon (IFN)-β is a commonly used therapy for relapsing remitting multiple sclerosis (RRMS). However its protective mechanism is still unclear and the failure of many patients to respond has not been explained. We have found that IFN-β suppressed IL-23 and IL-1β production and increased IL-10 production by human dendritic cells (DC) activated with the TLR2 and dectin-1 agonist zymosan. Furthermore, IFN-β impaired the ability of DC to promote IL-17 production by CD4(+) T cells, but did not affect IFN-γ production. IFN-β induced IL-27 expression by DC, and neutralisation of IL-27 abrogated the suppressive effects of IFN-β on zymosan-induced IL-1 and IL-23 production and the generation of Th17 cells in vitro. Complementary in vivo studies in a mouse model showed that treatment with IFN-β enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE). In addition, the significant suppressive effect of IFN-β on the ability of DC to promote Th17 cells was lost in cells from IL-27 receptor deficient mice. Finally, we showed that PBMC from non-responder RRMS patients produced significantly less IL-27 in response to IFN-β than patients who responded to IFN-β therapy. Our findings suggest that IFN-β mediates its therapeutic effects in MS at least in part via the induction of IL-27, and that IL-27 may represent an alternative therapy for MS patients that do not respond to IFN-β.

The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS‐29 physical)

Aim: The aims of this study were to determine the reliability, responsiveness and minimally important change score of the Multiple Sclerosis Impact Scale (MSIS)-29 physical using the Expanded Disability Status Scale (EDSS) as an anchor measure. Methods: 214 patients with multiple sclerosis (MS) (EDSS 0–8.5) had concurrent MSIS-29 and EDSS assessments at baseline and at up to 4 years of follow-up. Results: 116 patients had unchanged EDSS scores. Stability of the MSIS-29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0–5.0 than in the 31 patients with EDSS 5.5–8.5 in whom the MSIS-29 physical score fell by 8 points, a response shift phenomenon. A floor effect for the MSIS-29 was observed in 5% of stable patients at both time points. 98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS-29 physical (r = 0.523, p<0.0001). Effect sizes for MSIS-29 physical change were moderate to large. Using receiver operating characteristic curves, the MSIS-29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges. For EDSS range 5.5–8, a change score of 8 had a sensitivity of 87% and specificity of 67%. For EDSS 0–5.0, a change score of 7 had a sensitivity of 78% and a specificity of 51%. Conclusions: The MSIS-29 physical performs well over time, and is suitable for use in trials; a minimal change score of 8 points in the MSIS-29 is clinically significant.

'Neurophobia'--attitudes of medical students and doctors in Ireland to neurological teaching.

(i) To determine whether neurology is the medical specialty with which Irish students and doctors have most difficulty, (ii) appraise attitudes towards how neurology is taught, and (iii) suggest ways teaching might be improved. A questionnaire on medical teaching was given to 457 medical students and junior doctors in Ireland. Perceived difficulties with neurology compared with seven other medical specialties were analysed. Other aspects of teaching were assessed including why neurology is perceived as difficult and ways teaching could be improved. Neurology was perceived as the most difficult of the eight medical specialties assessed. Participants felt they learned most at bedside tutorials with surprisingly few learning online. Neurology was perceived as difficult because of insufficient exposure to the subject, lack of teaching, and perceived complexity. Neurology teaching could be improved by increasing the number of bedside tutorials and by greater exposure to neurological patients for the students in clinical training. Medical students and doctors find neurology difficult. The teaching of neurology is reported as moderate to poor. The reasons for this are wide ranging but an emphasis on increased numbers of tutorials and greater integration of pre‐clinical neurology to clinical years would improve teaching.

Does natalizumab therapy worsen neuromyelitis optica

We report 3 cases of continuing disease activity and possible exacerbation of neuromyelitis optica (NMO) on natalizumab. ### Case reports. #### Case 1. A 33-year-old woman presented in June 1995 with optic neuritis, followed by left hemiparesis. Multiple sclerosis (MS) was diagnosed and she was